Vortrag (Online-Veranstaltung)
Discovery of the TASK-1 and TASK-3 Channel Blocker BAY 2586116 for the Treatment of Obstructive Sleep Apnea (OSA)
Dr. Michael Hahn
Bayer
Discovery of the TASK-1 and TASK-3 Channel Blocker BAY 2586116 for the Treatment of Obstructive Sleep Apnea (OSA)
Michael G. Hahn,
Bayer AG, Pharmaceuticals, Medicinal Chemistry Wuppertal, Germany
TWIK-related acid-sensitive potassium (TASK) channels—members of the two pore domain potassium (K2P) channel family are found in neurons, cardiomyocytes and vascular smooth muscle cells, where they are involved in the regulation of heart rate, pulmonary artery tone, sleep/wake cycles and responses to volatile anaesthetics. K2P channels regulate the resting membrane potential, providing background K+ currents controlled by numerous physiological stimuli, such as pH in case of TASK. As recently published, the unique inner X-gate1 enables TASK channels to bind inhibitors with high affinity, extraordinary selectivity and extremely slow compound washout rates, which make these inhibitors attractive chemical starting points for the treatment of sleep apnea. Here we present a chain of translatability from a classical target driven drug discovery approach to represent a molecular association between a phenotypic in vivo disease model and human disease for OSA.
Initially, ultra-high throughput screening led to the identification of a novel highly potent and selective TASK-1/TASK-3 blocker class. Medicinal Chemistry efforts led to the lead structure BAY 1000493 (1) showing the required PK properties with high clearance and short half-life to avoid any systemic side effect. However, only moderate and short in vivo efficacy in the OSA pig model2 was observed after nasal application. Consequently, our optimization strategy focused on improving in vivo efficacy and duration of action in the OSA-pig model. Finally, further extensive chemical optimization culminating in the identification of BAY 2586116 (2), which was in Phase II for the treatment of OSA3. The discovery of BAY 2586116 (2) and the structural activity relationship within this class will be presented.
References
1. Rödström, K.E.J.; Kiper, A.K.; Zhang, W.; Rinne, S.; Pike, A.C.W.; Goldstein, M.; Conrad, L.J.; Delbeck, M.; Hahn, M.G.; Meier, H.; Platzk, M.; Quigley, A. Speedman, D.; Shrestha, L.; Mukhopadhyay, S.M.M.; Burgess-Brow, N.A.; Tucker, S.J.; Müller, T.; Decher, N.; Carpenter, E.P.; Nature 2020, 582, 443-447.
2. Wirth, K.J.; Steinmeyer, K.; Ruetten, H.; Sleep. 2013, 36, 699-708.
3. Osman, A.M.; Mukherjee, S.; Altree, T.J.; Delbeck, M.; Gehring, D.; Hahn, M.; Lang, T.; Xing, C.; Mueller, T.; Weimann, G.; Eckert, D.J.; Chest, 2023, 163(4), 953-965.
Michael G. Hahn,
Bayer AG, Pharmaceuticals, Medicinal Chemistry Wuppertal, Germany
TWIK-related acid-sensitive potassium (TASK) channels—members of the two pore domain potassium (K2P) channel family are found in neurons, cardiomyocytes and vascular smooth muscle cells, where they are involved in the regulation of heart rate, pulmonary artery tone, sleep/wake cycles and responses to volatile anaesthetics. K2P channels regulate the resting membrane potential, providing background K+ currents controlled by numerous physiological stimuli, such as pH in case of TASK. As recently published, the unique inner X-gate1 enables TASK channels to bind inhibitors with high affinity, extraordinary selectivity and extremely slow compound washout rates, which make these inhibitors attractive chemical starting points for the treatment of sleep apnea. Here we present a chain of translatability from a classical target driven drug discovery approach to represent a molecular association between a phenotypic in vivo disease model and human disease for OSA.
Initially, ultra-high throughput screening led to the identification of a novel highly potent and selective TASK-1/TASK-3 blocker class. Medicinal Chemistry efforts led to the lead structure BAY 1000493 (1) showing the required PK properties with high clearance and short half-life to avoid any systemic side effect. However, only moderate and short in vivo efficacy in the OSA pig model2 was observed after nasal application. Consequently, our optimization strategy focused on improving in vivo efficacy and duration of action in the OSA-pig model. Finally, further extensive chemical optimization culminating in the identification of BAY 2586116 (2), which was in Phase II for the treatment of OSA3. The discovery of BAY 2586116 (2) and the structural activity relationship within this class will be presented.
References
1. Rödström, K.E.J.; Kiper, A.K.; Zhang, W.; Rinne, S.; Pike, A.C.W.; Goldstein, M.; Conrad, L.J.; Delbeck, M.; Hahn, M.G.; Meier, H.; Platzk, M.; Quigley, A. Speedman, D.; Shrestha, L.; Mukhopadhyay, S.M.M.; Burgess-Brow, N.A.; Tucker, S.J.; Müller, T.; Decher, N.; Carpenter, E.P.; Nature 2020, 582, 443-447.
2. Wirth, K.J.; Steinmeyer, K.; Ruetten, H.; Sleep. 2013, 36, 699-708.
3. Osman, A.M.; Mukherjee, S.; Altree, T.J.; Delbeck, M.; Gehring, D.; Hahn, M.; Lang, T.; Xing, C.; Mueller, T.; Weimann, G.; Eckert, D.J.; Chest, 2023, 163(4), 953-965.